title: Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma.
abstract: One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.
authors.affiliation: Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Barbara
authors.initials: B
authors.lastname: Fuchs
authors.forename: Lisa
authors.initials: L
authors.lastname: Sjöberg
authors.forename: Gunnar P
authors.initials: GP
authors.lastname: Nilsson
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.forename: Navin L
authors.initials: NL
authors.lastname: Rao
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
mesh_terms: D000085:Acetates / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000473:pathology; D003521:Cyclopropanes; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000627:therapeutic use; D006967:Hypersensitivity / Q000473:pathology*; D007213:Indomethacin / Q000627:therapeutic use; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D010047:Ovalbumin / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000627:therapeutic use; D011738:Pyrilamine / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D013440:Sulfides
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D006633:Histamine Antagonists; D020024:Leukotriene Antagonists; D011448:Prostaglandin Antagonists; D011804:Quinolines; D013440:Sulfides; D010047:Ovalbumin; D011738:Pyrilamine; C093875:montelukast; D007213:Indomethacin